AbstractPost-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including cell division, immune responses, and apoptosis. Ubiquitin-mediated control over these processes can be reversed by deubiquitinases (DUBs), which remove ubiquitin from target proteins and depolymerize polyubiquitin chains. Recently, much progress has been made in the DUBs. In humans, the ovarian tumor protease (OTU) subfamily of DUBs includes 16 members, most of which mediate cell signaling cascades. These OTUs show great variation in structure and function, which display a series of mechanistic features. In this review, we provide a comprehensive analysis of current progress in character, structure and function of OTUs, such as the substrate specificity and catalytic activity regulation. Then we discuss the relationship between some diseases and OTUs. Finally, we summarize the structure of viral OTUs and their function in immune escape and viral survival. Despite the challenges, OTUs might provide new therapeutic targets, due to their involvement in key regulatory processes.